Tackling Both Stress and Depression A new potential depression treatment with minimal side effects

New research has demonstrated the antidepressant and antistress effects of KNT-127, a potent delta opioid receptor (DOP) agonist, in a mouse model. The study showed that KNT-127 reduced inflammation and neonatal neuronal death in the hippocampus, potentially offering a more effective and faster-acting treatment for depression with fewer side effects than conventional antidepressants.

Researchers have developed a potential treatment for depression that demonstrates both stress-relieving and antidepressant effects with minimal side effects.

Millions of individuals around the world are struggling with depression resulting from psychological stress. However, most existing antidepressant drugs suffer from limitations, such as slow action, potential resistance development and severe side effects, which call for more effective treatment options.

Delta opioid receptors (DOPs) have been identified as instrumental in the progression of depression and related disorders. Past research has shown that PDO agonists (agents that bind to PDOs, mimicking the action of the naturally occurring substance) show better efficacy and fewer side effects than most conventional antidepressants. Recent investigations have revealed KNT-127, a potent DOP agonist, which demonstrates significant antidepressant efficacy, rapid onset of action, and minimal side effects. However, the precise mechanism of its operation remains not well understood.

To this end, Prof. Akiyoshi Saitoh, Mr. Toshinori Yoshioka, Jr. Associate Prof. Daisuke Yamada and Prof. Eri Segi-Nishida, Tokyo University of Sciences, together with Prof. Hiroshi Nagase of the University of Tsukuba, set out to evaluate the therapeutic and preventive effects of KNT-127 in a mouse model with depression. The results of this study were recently published in the journal Neuropharmacology.

Explaining the motivation behind their study, explains prof. Saitoh, we previously found that delta-opioid receptor agonists (DOPs) can act quickly and have a low risk of side effects compared to existing drugs. Therefore, we have been working on their clinical development as a new treatment strategy for depression. In this study, we attempted to elucidate the mechanism of the antidepressant effects of KNT-127, a selective DOP agonist, in a mouse model of depression.

Japanese researchers demonstrate that a PDO agonist, KNT-127, alters the hypothalamic-pituitary-adrenal axis, hippocampal neurogenesis, and neuroinflammation, to show therapeutic and prophylactic effects. Credit: 202102 Frontal plan of the cerebral hippocampus from the DataBase Center for Life Sciences (DBCLS)

The hypothalamic-pituitary-adrenal axis, hippocampal neurogenesis, and neuroinflammation are considered major factors in the processes leading to the development of depression. Therefore, understanding the effect of KNT-127 on the above parameters was crucial in decoding its underlying working principle.

To this end, Prof. Saitoh and his team created the mouse model of depression called chronic social defeat stress (cVSDS) mice, by exposing five-week-old male mice to extreme psychological stress for 10 minutes a day, repeated for 10 days. Subsequently, KNT-127 was administered to mice both during (10 days) and after (28 days after) the stress period, to evaluate its efficacy.

They observed that prolonged administration of KNT-127 during (antistress effect) and after the period of stress (antidepressant effect), significantly improved social interaction and serum corticosterone (a hormone secreted under stress in mice) levels in cVSDS mice. . Furthermore, administration of KNT-127 during stress suppressed stress-induced neonatal neuronal death in the hippocampus, rather than increasing neurogenesis or the formation of new neurons. In contrast, when administered after stress, KNT-127 did not affect the survival rate of newborn neurons at all. Furthermore, unlike conventional antidepressants, KNT-127 did not affect neurogenesis even under stress-free conditions.

Psychological stress increases the number of microglia and activated microglia in the brains of cVSDS mice. Interestingly, in both delivery models, KNT-127 suppressed microglial activation and thereby reduced inflammation in the hippocampus.

Simply put, during and after the period of stress, KNT-127 prevents neuronal inflammation and reduces neonatal neuronal death without affecting neuron formation to exert antistress and antidepressant effects, respectively. However, more research is needed for a better understanding of PDO agonists and the mechanism behind their antidepressant effects.

The stress-relieving effect of KNT-127 may offer additional benefits for patients during treatment. Prof. Saitoh elaborates: Depressed patients often face situations where they cannot avoid stressful environments, even during treatment. Therefore, we believe that the additional stress-relieving effect during the treatment period has important clinical significance.

Prof. Saitoh concludes by sharing their vision for the future. We expect the successful clinical development of DOP agonists to greatly expand options for the treatment of depression in the future.

Reference: KNT-127, a selective delta-opioid receptor agonist, shows beneficial effects in the hippocampal dentate gyrus of a mouse model of chronic indirect social defeat stress by Toshinori Yoshioka, Daisuke Yamada, Eri Segi-Nishida, Hiroshi Nagase, and Akiyoshi Saitoh March 30, 2023, Neuropharmacology.
DOI: 10.1016/j.neuropharm.2023.109511

This work was supported by Cyclic Innovation for Clinical Empowerment as part of the Japan Agency for Medical Research and Development (AMED).